3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-benzopyran-6-yl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

In a one-generation reproduction toxicity study (Krasavage 1977), rats were fed up to 2.0% d-alpha-tocopheryl poly(ethylene glycol) 10000 succinate (corresponding to 800 mg/kg bw/day ((using default values of 20 g food /day and a body weight of 0.5 kg ( REACH guidance Chapter R.8: Characterisation of dose [concentration]-response for human health (Table R8 -17)).

No apparent differences in reproductive indices were seen between controls and treated groups of parents. Mean gestation period, litter size, sex ratio, and mortality of pups and parents were unaffected by the test substance.

Hematology and clinical chemistry done after 255 days of treatment revealed no toxicologic differences between control and high dose group. None of the organ weights (neither absolute nor relative) of the treated groups were significantly different from control. Microscopic examination of tissues of high dose and control F0 and F1b animals revealed no morphological changes that were attributable to ingestion of the test substance. Ingestion of the test substance had no effect on body weight gain of the pups.

No two-generation reproduction toxicity study is available for vitamin E. However, after the evaluation of the reproduction toxicity data and other repeated dose toxicity data it is concluded that a two-generation study is not needed (as discussed below).

In addition, in the repeated dose toxicity studies (Morrissey;1988 and Yang and Desai;1977) also no effects were noted for the reproductive organs (ovary, uterus, prostate, epididymis and testes). There was no significant effect of treatment with the test substance on body weight, absolute and relative right cauda weight, absolute and relative right epididymis weight, relative right testis weight, sperm motility, sperm density, or incidence of abnormal sperm (Morrissey, 1988). In an another study female rats were fed for 3 months by diet prior to mating with untreated males (Yang and Desai. 1977). This study described effects in the highest group tested at 10,000 ppm:only 1/5 rat of the high-dose group was pregnant, while pregnancy was 100% in all othergroups (treated at 25, 250 and 2500 ppm).

The one-generation study revealed no toxicological differences in rats of d-alpha-tocopheryl poly(ethylene glycol) 10000 succinate treated group compared to the control group and no effects were observed in rats of the treated group after microscopic examination or in body weight gain of the pups. Taken together, these data are considered sufficient to cover the endpoint effects on reproduction.

Short description of key information:
In a one-generation reproduction rat toxicity study (comparable to OECD 415), the reproductive indices of the treated groups were unaffected and the offspring developed normally. The NOAEL was 800 mg/kg (corresponding to 2%).

Effects on developmental toxicity

Description of key information

In a teratogenicity study with rats and rabbits (equivalent or similar to OECD Guideline 414, pre-GLP), no significant difference in malformations between the control and the treated groups. The NOAEL is >1600 mg/kg bw/day for both species.

Additional information

In a teratogenicity study, rats were applied by gavage up to 1600 mg/kg bw/day DL-Alpha-Tocopheryl acetate (FDA, 1973).

There were no significant differences in any parameter between the groups treated with the test substance. No dose-response relationship was noted. Malformations of the sternebrae, ribs, vertebrae, skull, and extremities were recorded. However, the incidences of these malformations in vitamin E-treated groups were not significantly different from those observed in sham-treated control. Soft tissue variations in the tocopheryl acetate groups were distributed over all groups without indicating any dose-response. These variations included cardiomegaly (3 fetuses), anophthalmia (1 fetus), hydrocephalus (3 fetuses), gastroschisis (2 fetuses), apulmonism (1 fetus), and petechiae (1 fetus). No soft tissues are reported for the sham-treated control fetuses. In the positive control group treated with Aspirin, the expected statistically significant increase in the incidence of skeletal malformations and soft tissue variations was observed.

The teratogenic activity of DL-Alpha-Tocopheryl acetate was also investigated in rabbits (FDA, 1973). The test substance was administered by gavage at dose levels of 0 (sham-treated control group), 16, 74.3, 345, and 1600 mg/kg bw/d. The administration of up to 1600 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. In addition, no teratogenic effects were seen in mice and hamsters (FDA, 1973).

Justification for classification or non-classification

Based on the available data, DL-Alpha-Tocopheryl acetate

does not need to be classified for effects on fertility and developmental toxicity according to Annex I of Directive 67/548/EEC and according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.